Directory UMM :Data Elmu:jurnal:B:Biological Psichatry:Vol48.Issue7.2000:

Are Schizophrenic and Bipolar Disorders Related?
A Review of Family and Molecular Studies
Wade H. Berrettini
Schizophrenic and bipolar disorders are similar in several
epidemiologic respects, including age at onset, lifetime
risk, course of illness, worldwide distribution, risk for
suicide, gender influence (men and women at equal risk
for both groups of disorders), and genetic susceptibility.
Despite these similarities, schizophrenia and bipolar disorders are typically considered to be separate entities,
with distinguishing clinical characteristics, non-overlapping etiologies, and distinct treatment regimens. Over the
past three decades, multiple family studies are consistent
with greater nosologic overlap than previously acknowledged. Molecular linkage studies (conducted during the
1990s) reveal that some susceptibility loci may be common
to both nosologic classes. This indicates that our nosology
will require substantial revision during the next decade, to
reflect this shared genetic susceptibility, as specific genes
are identified. Biol Psychiatry 2000;48:531–538 © 2000
Society of Biological Psychiatry
Key Words: Genetic linkage, schizophrenia, bipolar disorder, family studies

Introduction

T

he hypothesis that schizophrenic (SZ) and bipolar
(BP) syndromes share some genetic risk factors is the
subject of this article. To consider this question, epidemiologic, family, and molecular linkage studies are reviewed. If there is shared genetic risk for these syndromes,
then we might reasonably expect some similarities in
epidemiology. Epidemiologic characteristics common to
both BP and SZ disorders are reviewed. Further, if there is
shared genetic risk for these syndromes, then family
studies should reveal some overlap in familial aggregation.
Schizophrenic and BP family studies reveal partial overlap
in risk for illness. Finally, if there is shared genetic risk,
some susceptibility loci (identified through linkage studies) should be common to both disorders. A review of BP
From the Department of Psychiatry and the Center for Neurobiology and Behavior,
University of Pennsylvania, Philadelphia.
Address reprint requests to Wade H. Berrettini, M.D., Ph.D., Director, Center for
Neurobiology and Behavior, University of Pennsylvania School of Medicine,
Room 111, Clinical Research Building, 415 Curie Blvd, Philadelphia PA
19104.

Received January 12, 2000; revised March 18, 2000; accepted March 20, 2000.

© 2000 Society of Biological Psychiatry

and SZ molecular linkage studies reveals several genomic
regions potentially relevant to both nosological classes. It
is concluded that SZ and BP disorders share some genetic
risk factors. It is not the thesis of this article that the two
nosologic categories represent a single entity or a continuum, but that the two groups of disorders are more closely
related than previously considered.

Epidemiologic Similarities
Bipolar and SZ disorders are common, chronic groups of
illnesses that share many epidemiologic features (for
review see Nurnberger and Berrettini 1998). They each
affect ;1% of the world’s populations, occurring at
approximately the same rate across all continents. Although they are common in young adulthood (onset of
illness typically occurs prior to age 25 years), these
disorders are unusual in prepubertal children. Thus, BP
and SZ diagnostic categories have similar ages at onset.

These two nosologic classes describe psychotic disorders
that often assume episodic courses of illness (with partial
to complete remissions and clear exacerbations), although
relatively chronic, unremitting SZ disorders are frequently
encountered. With rare exceptions, BP and SZ disorders
are lifelong conditions. In general, once DSM-4 criteria
for BP or SZ diagnoses are met, the disorder persists
through life. Spontaneous and lifelong (permanent) remissions of either BP or SZ disorders are very unusual.
Increased risk for suicide is another characteristic that
these two groups of disorders share. Both syndromes
affect men and women equally. Familial aggregation has
been demonstrated repeatedly for SZ and for BP. Twin and
adoption studies of BP and SZ disorders are consistent
with substantial heritability. From twin studies, estimates
of heritability for these disorders are quite similar: ;50%
for SZ disorders and ;65% for BP disorders.
There are, however, clear clinical distinctions between
these two nosologic categories, such that their classic
presentations are not often mistaken for one another. The
majority of BP individuals benefit from lithium therapy,

whereas few persons with SZ are helped substantially.
Bipolar disorder manifests as a disturbance of mood,
whereas SZ is a primary disorder of cognition. There are
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several electrophysiologic (Adler et al 1999; Freedman et
al 1997; Ford 1999) abnormalities in SZ that do not
characterize BP disorder. In the context of these shared
epidemiologic characteristics, is there any evidence that
these two syndromal classifications share genetic risk
factors? If this hypothesis is true, then we would expect to
find increased risk for SZ syndromes among the firstdegree relatives of BP probands, and, conversely, increased risk for BP syndromes among the first-degree

relatives of SZ probands.

Review of Family Studies
A review of BP family studies reveals the following:
First-degree relatives of BP probands are at increased risk
for several nosologically related disorders: BPI, BPII
(hypomanic and recurrent unipolar [RUP] episodes in the
same person), schizoaffective (SA) and RUP (Angst et al
1980; Baron et al 1983; Gershon et al 1982; Helzer and
Winokur 1974; James and Chapman 1975; Johnson and
Leeman 1977; Maier et al 1993; Weissman et al 1984;
Winokur et al 1982, 1995). Despite numerous careful
investigations, no study of the first-degree relatives of BP
probands reveals increased risk for SZ.
Similarly, a review of SZ family studies reveals that the
first-degree relatives of SZ probands are at increased risk
for SZ, SA, and RUP disorders (Gershon et al 1988; Maier
et al 1993). Kendler et al (1993) describe increased risk for
psychotic affective illness among relatives of SZ probands. Despite numerous carefully conducted investigations, no family study of SZ reports increased risk for BP
disorders among first-degree relatives of SZ probands;

however, the first-degree relatives of SZ probands and the
first-degree relatives of BP probands are at increased risk
for SA and RUP disorders. The overlap in elevated risk for
SA and RUP diagnoses is evident. Therefore, these family
studies are consistent with partial overlap in familial
susceptibility for BP and SZ disorders; however, these
family studies are limited in size and power. A small
increase in risk for SZ among the first-degree relatives of
BP probands might have been undetected. There is a need
for large, systematic family studies of SA probands.
It is argued here that the epidemiologic and family study
similarities suggest that these two groups of disorders are
more closely related than previously considered. Because
BP and SZ nosologic classes each represent multiple
disease entities (with some clinical similarities), it is
hypothesized here that some of these disease entities might
produce syndromes that may be assigned to either nosologic group (BP or SZ), depending on the genetic background on which they arise. This hypothesis implies that
the partial overlap in epidemiologic and family studies
may originate in genetic susceptibility.

Given the evidence for partial overlap in familial
susceptibility for BP and SZ disorders, one may ask
whether the overlap may have genetic origins. If this
partial overlap is genetic, then molecular linkage studies of
BP and SZ disorders should have detected some loci in
common. The next section will review BP and SZ molecular linkage studies.

Review of BP and SZ Molecular
Linkage Studies
In genetic linkage analysis of common complex disorders,
failure of subsequent studies to confirm previously nominated susceptibility loci has become commonplace. This
is as true for diabetes mellitus (Concannon et al 1998;
Hanis et al 1996) as it is for SZ and BP disorders. This
failure to confirm has multiple origins. The most important
origin is power to detect a susceptibility locus of limited
effect size in the presence of genetic heterogeneity. Common, complex disorders (e.g., asthma, epilepsy, diabetes
mellitus, and SZ disorders) are most probably the manifestations of multiple susceptibility loci, within an affected
individual, which interact with each other and the environment to produce these well-known syndromes. For
these disorders, no single susceptibility locus has a major
effect on risk for illness in a majority of the ill population.

Loci that increase risk by factors greater than 2 are unusual
for common, complex disorders. Despite Herculean efforts
in numerous disorders, only two loci that increase risk by
a factor of .2 in a large fraction of ill people have been
detected: one is HLA for insulin-dependent diabetes mellitus (increased risk 5 ;3 [Davies et al 1994]; the other is
apolipoprotein E in late onset Alzheimer’s disease (Corder
et al 1993; Mayeux et al 1993; Tsai et al 1994). Substantial
sample sizes are required to detect such loci which
increase risk by factors of #2. As Hauser et al (1996) have
shown, ;400 affected sibling pairs are needed to have
.90% power to detect (p , .0001 or log of the odds ratio
[LOD] . 3) loci that increase risk by a factor of 2. No
single linkage study of BP or SZ disorders published in the
1990s has exceeded this sample size, although metaanalyses of multiple independent data sets have larger
sample sizes.
A second major reason for lack of confirmation is a
failure to appreciate the limited ability of linkage methods
to localize susceptibility genes to small (;5 million base
pairs of DNA or ;5 cM) genomic regions. Linkage
analyses of complex traits are not able to localize disease

genes to narrow (,5 cM) genomic regions with currently
available (,2000 affected sibling pairs) sample sizes
(Kruglyak and Lander 1995). For example, the BRCA1
gene was cloned (Futreal et al 1994) ;15 cM from the
peak of the original LOD score (Hall et al 1990). Roberts

Review of Family and Molecular Studies

et al (1999) simulated linkage studies for a complex,
genetically heterogeneous disorder. They found that the
95% confidence interval for location estimates (from
simulated linkage studies of 200 affected sibling pairs) is
;30 cM.
A third major reason for lack of confirmation in linkage
studies of common complex disorders has been delineated
by Suarez et al (1994), who conducted simulation studies
to evaluate the power to replicate linkage. They simulated
linkage data for a complex disease caused in part by six
equally frequent independent (unlinked) disease loci. They
found that a larger sample size was required to confirm

linkage of a previously detected locus, because independent pedigree samples might (through sampling variation)
contain an over-representation of different susceptibility
loci, rather than the locus initially detected. Given that
investigators often draw their pedigrees from different
ethnic backgrounds (in which prevalence of a particular
susceptibility locus might vary), sampling variation is an
important origin of confirmation failure. Thus, expectations of universal agreement (even when sample size is
adequate) regarding susceptibility loci for common complex traits are unrealistic.
Although validity (through confirmation) of previously
reported linkages is difficult for common, complex disorders, some guidelines for validity have been proposed
(Lander and Kruglyak 1995; Lander and Schork 1994).
These guidelines include a threshold for an initial report of
“significant” linkage (LOD score 5 ;3.6 or nominal p 5
;.00002) and for confirmation (LOD score 5 1.2 or p 5
;.01). These guidelines should limit false positives to less
than 5%. These thresholds for statistical significance
assume analysis of one affection status model (phenotypic
definition of caseness), for example BPI, SA, and BPII
disorders. If several (overlapping) affection status models
are used in multiple linkage analyses (dominant, recessive,

and nonparametric approaches) then some “Bonferroni”
correction for multiple hypothesis testing may be
necessary.
The Lander and Kruglyak (1995) guidelines for statistical significance in linkage studies (LOD score 5 ;3.6 or
nominal p 5 ;.00002 and one confirmation LOD score 5
1.2 or p 5 ;.01) were determined through simulation to
represent a false positive rate less than 5% (one in 20
genome scans). It seems logical that three or more independent studies, each with p # .001, should provide a
similar level of statistical confidence, although this has not
been tested through simulation.
If analysis is limited to “confirmed” BP and SZ linkage
susceptibility loci, then the risk for false positive conclusions should be minimized. Our approach will have two
facets. First, confirmed BP susceptibility loci will be
examined, asking the question: Is there at least one report,

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2000;48:531–538

533

in this same region, of linkage to SZ with a p value #
.001? Second, we will examine all confirmed SZ susceptibility loci, asking the question: Is there at least one
report, in this same region, of linkage to BP disorder with
a p value # .001?

Evidence for Linkage of BP and SZ
Disorders to 18p11

Berrettini et al (1994, 1997) reported evidence for a BP
susceptibility locus on 18p11 using affected sibling pair
(ASP) and affected pedigree member (APM) methods
(p 5 1024 2 1026). Independent evidence of confirmation
of this finding was reported by Stine et al (1995), Nothen
et al (1999), and Turecki et al (1999). Evidence for linkage
was found most often among those families with paternally transmitted illness (Gershon et al 1996; Nothen et al
1999; Stine et al 1995). As part of Genetic Analysis
Workshop #10, independent BP chromosome 18 linkage
data sets, including ;1200 samples, were assembled for
meta-analyses (Goldin et al 1997). An affected sibling pair
(n 5 382 sibling pairs) meta-analysis yielded p 5 2.8 3
1028 at marker D18S37 (Lin and Bale 1997).
Schwab et al (1998) employed ;20 chromosome 18
markers in a linkage study of 59 multiplex German and
Israeli SZ pedigrees, in which there were 24 affective
disorder cases (two were BP). When these data were
analyzed in two-point parametric methods, the maximum
LOD score was 3.1 at D18S53. A multipoint nonparametric analysis revealed p 5 .002, at D18S53.
One may be concerned that Schwab et al (1998) studied
kindreds whose probands were misdiagnosed or unusual in
some undetected characteristics; however, the SZ kindreds
studied for 18p11 linkage by Schwab et al (1998) are not
nosologically or genetically distinct from other multiplex
SZ kindreds. If the SZ kindreds of Schwab et al (1998,
1995, 1999) were nosologically unique (perhaps misclassified affective disorder kindreds), then one would not
expect to find confirmations of other SZ loci in those
kindreds. These kindreds show linkage to chromosome 6p
(Schwab et al 1995), as reported in other series of
multiplex SZ kindreds (Straub et al 1995; Maziade et al
1997; Moises et al 1995). Similarly, Faraone et al (1998)
and Straub et al (1998) report SZ linkage to 10p14, as did
Schwab et al (1999). Nosological misclassification does
not explain the chromosome 18p11.2 linkage to SZ detected by Schwab et al (1998). Thus, one region of
potential overlap in susceptibility for BP and SZ syndromes is 18p11.2.

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Evidence for Linkage of SZ and BP
Disorders to 13q32
Lin et al (1997) observed a LOD score of 2.58 (p 5
;0.001) at 13q32 markers (D13S122 and D13S128) in a
linkage study of SZ. Blouin et al (1998), studying independent SZ kindreds, report a p value of .00002 (LOD 5
3.6) at the 13q32 marker, D13S174, in 54 SZ kindreds.
Subsequently, Brzustowicz et al (1999) confirmed these
reports in 21 Canadian SZ families, with a maximal LOD
score of 3.92 at the 13q marker D13S793. Thus, there are
at least three independent reports, with substantial statistical significance, consistent with a 13q32 SZ susceptibility locus.
Detera-Wadleigh et al (1999) described linkage (p 5
.00003) to 13q32 markers (D13S1271 and D13S779) in 22
BP kindreds of European ancestry. One may be concerned
that the kindreds studied by Detera-Wadleigh et al (1999)
were misclassified; however, these kindreds reveal evidence for linkage to 21q21 (Detera-Wadleigh et al 1996),
a BP susceptibility locus (see below). Kelsoe et al (1998)
reported linkage of BP disorder to 13q32 markers, with
LOD 5 2.4 at D13S154. Thus, the 13q32 region has a
confirmed SZ susceptibility locus, and there are statistically impressive reports of linkage at this locus in BP
disorder.

Evidence for Linkage of SZ and BP
Disorders to 10p14
In a recent series of articles, Faraone et al (1998), Straub
et al (1998) and Schwab et al (1998) reported evidence for
linkage of SZ to 10p14 markers. Faraone et al (1998)
reported p 5 .0004 for marker D10S1423 and p 5 .0006
for D10S582, in a study of 43 American SZ kindreds of
European ancestry. Straub et al (1998), in a study of Irish
SZ kindreds, reported p 5 .006 for this region in a
multipoint analysis. For marker D10S582, Schwab et al
(1998) reported p 5 .0058 for German SZ kindreds. These
three groups of investigators studied independent sets of
kindreds that were of general European ancestry. Although
no single report was consistent with significant linkage
(p 5 .00002), these three reports probably constitute a true
positive linkage, nonetheless.
Foroud et al (2000) studied BP kindreds from the
National Institute of Mental Health Genetics Initiative.
They found LOD 5 2.5 (p 5 .001) for marker D10S1423.
Thus, the 10p14 region may represent a third region of the
genome at which there is shared susceptibility for BP and
SZ disorders.

Evidence for Linkage of SZ and BP
Disorders to 22q11-13
Lachman et al (1996), Edenberg et al (1997), Kelsoe et al
(1998), and Detera-Wadleigh et al (1997) described evi-

W.H. Berrettini

dence for a BP susceptibility locus on chromosome 22q1113, near the velo- cardiofacial syndrome (VCFS) locus.
Kelsoe et al (1999) report an LOD score of 3.8 at
D22S278. Detera-Wadleigh et al (1999) report p 5 .008
for markers in this region. This VCFS has been associated
with microdeletions of the 22q region. These individuals
have a psychosis in ;30% of cases. The syndromal form
of the psychosis has been termed schizophrenia-like (Pulver et al 1994b), whereas others have described it in terms
of bipolar disorder (Carlson et al 1997; Papolos et al
1996). This region of 22q has been implicated in risk for
schizophrenia (Gill et al 1996; Pulver et al 1994a). This
region represents a fourth area of overlap for BP and SZ
susceptibility loci.

Confirmed Susceptibility Loci Unique to BP
Disorders
Although there are four regions of the genome (18p11.2,
13q32, 22q11-13, and 10p14) where BP and SZ susceptibility loci may overlap, the reader should not be left with
the impression that this is true for all confirmed BP
susceptibility loci. In fact, there are multiple other confirmed BP susceptibility loci at which no report is consistent with a SZ susceptibility locus. The “uniquely BP”
susceptibility loci are summarized as follows.
Morissette et al (1999) reported evidence for a chromosome 12q24 BP susceptibility locus, detected through study
of a population isolate (French ancestry) from the Saguenay
River region of Quebec province. The LOD score exceeds 8
in a recent abstract (Barden et al 1998), clearly exceeding
guidelines for significant linkage. Independent confirmation
of this BP susceptibility locus has been observed by Ewald et
al (1998a) in a study of Danish BP kindreds, with LOD 5
3.3. Detera-Wadleigh et al (1999) observed modest support
for this locus in a study of 22 American kindreds of European
origin. There have been no reports of SZ linkage to this
region. Thus, the 12q24 region represents a confirmed BP
susceptibility locus.
Straub et al (1994) initially described linkage of BP
disorder to 21q21 markers, in a study of American and
Israeli BP kindreds. One BP pedigree with a LOD score of
3.41 was reported from a series of 57 BP kindreds; further,
nonparametric analysis provided evidence for linkage
(p , .0003 for the phosphofructokinase locus). An emendation of this original work has been published by Aita et
al (1999). A confirmation has been described in a twolocus analysis of genotypic data from 21q21 and 11p15.5
(Smyth et al 1996). This 21q21 BP susceptibility locus has
been confirmed by Detera-Wadleigh et al (1996), who
employed multipoint nonparametric analyses (p , .001).
Kwok et al (1999) described confirmatory evidence for
linkage to this region in nonparametric analyses. Kelsoe et
al (1999) reports an LOD of .2 in this region. Morisette

Review of Family and Molecular Studies

et al (1999) also report a confirmation for this locus in a
population isolate of French ancestry. There are no reports
of SZ susceptibility to this region, suggesting that the
21q21 region harbors a locus that increases risk for BP
disorder.
An extended Scottish kindred showed linkage (LOD 4.1
at D4S394) to 4p16 DNA markers (Blackwood et al 1996).
Confirmation of the 4p locus has been reported in a paper
by Nothen et al (1997), in which increased allele sharing
was noted at D4S394 (p 5 .0009). Another confirmation
was described by Ewald et al (1998b), who noted a LOD
of 2.0 at D4S394. Ginns et al (1998) reported linkage to
this region for a mental health locus, meaning absence of
any psychiatric disorder. This requires additional investigation. Thus, the 4p16 region has a confirmed BP susceptibility locus. No reports of SZ linkage are known.
A fourth region of the genome that harbors a BP
susceptibility locus is 18q22. Stine et al (1995) initially
reported linkage to this region in 28 American BP kindreds (LOD is 3.51 for D18S41) and the ASP method
(0.00002 at D18S41). In an extension of this work,
McMahon et al (1997) provided additional evidence for
linkage to 18q21-2 in 30 new BP kindreds. This locus may
have been detected by Freimer et al (1996) and McInnes et
al (1996) who studied Costa Rican BP kindreds. McInnes
et al (1996) described evidence for increased allele sharing
at some of the same markers identified by McMahon et al
(1997). For example, at D18S55, McMahon et al (1997)
reported a nonparametric LOD score of 2.2, whereas
McInnes et al (1996) at this same marker report a
maximum likelihood estimate of the LOD score as 1.67.
Although the genetic map position of greatest significance
for these two studies are not identical (see Roberts et al
1999), there is sufficient map location overlap to conclude
tentatively that the two studies detect the same locus.
In summary, there are four regions of the genome that
appear to harbor unique BP susceptibility loci, including
21q21, 18q22, 12q24, and 4p16. For each of these four
regions there are several consistent reports of linkage,
indicating that these loci are probably true positives.

Confirmed Susceptibility Loci Unique to SZ
Disorders
In parallel to the BP disorders linkage literature, there are
SZ susceptibility loci that appear to be unique to that
nosologic classification, in that there are no reports of BP
disorders linkage to these genomic regions. Straub et al
(1995) initially identified SZ linkage in Irish multiplex
families to 6p22-24. Confirmations were published by
Schwab et al (1995), who studied German SZ kindreds,
and by Moises et al (1995). Levinson et al (1996), in a
collaborative venture, noted support for this locus in a

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535

large data set. Maziade et al (1997) also confirmed this
locus. Although no single report among these studies
provides significant linkage (Lander and Kruglyak 1995),
there is sufficient evidence in the original report and the
several confirmations, that this is likely to be a true
positive SZ locus on 6p22-24. There are no molecular
reports of BP disorders linkage to this region.
A second “unique” SZ susceptibility locus is found on 8p.
Blouin et al (1998) reported evidence for a SZ locus at 8p22,
in 54 multiplex kindreds. The LOD score, assuming heterogeneity, was 4.5. Nonparametric analysis yielded p 5 .0001.
Brzustowicz et al (1999) studied 21 extended Canadian SZ
pedigrees with 8p markers. The maximum multipoint LOD
score was 2.1 at D8S136, providing an additional confirmation of an 8p22 SZ locus. Levinson et al (1996), in a
multicenter collaborative effort, reported independent results
(that did not include the pedigrees of Blouin et al 1998),
yielding p 5 .00018 in this same region of 8p22. Gurling et
al (1999), in a study of 13 extended European SZ kindreds,
reported an LOD of 3.6 for 8p22 markers. Thus, these reports
constitute a confirmed SZ linkage, and there is no report of
BP disorders linkage to this region.
A third unique SZ susceptibility locus may be found on
6q21 (Cao et al 1997; Martinez et al 1999). There is no
statistically robust (p $ .001) report of BP linkage at this
locus.

Summary
A review of epidemiology and family studies suggests
some similarities between SZ and BP disorders. Family
studies, in particular, suggest partial overlap in risk for SA
diagnoses and some affective disorders (Gershon et al
1988; Kendler et al 1993; Maier et al 1993). This overlap
is consistent with shared genetic risk.
A review of molecular linkage studies reveals evidence
for shared genetic loci at 18p11.2, 22q11-13, 13q32, and
10p14. This is consistent with the family studies. There
remain independent BP susceptibility loci at 18q22,
21q21, 4p16, and 12q24, where there are no prominent
reports of SZ susceptibility. Similarly, there are confirmed
SZ susceptibility loci at 6p22, 6q21, and 8p22, where there
are no reports of BP susceptibility. Thus, the molecular
reports are consistent with the family studies, in suggesting partial shared genetic risk. The confirmed BP and/or
SZ susceptibility loci, identified through linkage studies,
are summarized in Figure 1.
If there were only a single genomic region of overlap, this
might occur randomly; however, there are four genomic
regions of overlap for BP and SZ susceptibility loci, observations that are consistent with the family study data. It is
possible, however, that these regions of overlap are secondary to sources of error that are common to the several BP and

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References

Figure 1. Ideograms of human chromosomes are marked to the
right with B to indicate the location of susceptibility loci unique
to bipolar disorder, with S to indicate schizophrenic loci, and
with * for both bipolar disorder and schizophrenia.

SZ linkage studies. Although this seems improbable, it
should be considered carefully in future studies.
It is expected that novel genes, corresponding to these loci,
will be identified in the next several years. Direct study of
these susceptibility alleles will allow for correlation between
genotype and phenotype. Nosology for these disorders must
be redefined accordingly, and this will require that we
relinquish long-held (mis)conceptions about these disorders.
In the bright light of new genetic knowledge concerning the
origins of these disorders, we will be able to ask refined
questions concerning environmental risk factors. Because
environment drives gene expression, knowledge of the environmental risk factors will certainly enhance comprehension
at the molecular level. This complex evolution of our understanding of SZ and BP disorder will require several decades
at least. As a result of this effort, we can anticipate marked
improvements in the outcomes for these disorders, which
now shatter the lives of so many.
This article was prepared with the support of NIH Grant MH59553 and
a NARSAD Distinguished Investigator Award.
Aspects of this work were presented at the conference, “Bipolar
Disorder: From Preclinical to Clinical, Facing the New Millennium,”
January 19 –21, 2000, Scottsdale, Arizona. The conference was sponsored by the Society of Biological Psychiatry through an unrestricted
educational grant provided by Eli Lilly and Company.

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